Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapy

Abstract

The mTORC1 signaling pathway is a critical regulator of cell growth and is hyper activated in many different cancers. Rapamycin, an allosteric inhibitor of mTORC1, has been approved for treatment against renal cell carcinomas and is being evaluated for other cancers. Mechanistically, mTORC1 controls cell growth in part through its two well-characterized substrates S6K1 and 4E-BP1. In this review, we discuss the implications of a recent finding that showed differential inhibition of S6K1 and 4E-BP1 by rapamycin, leading to cell-type-specific repression of cap-dependent translation. We discuss potential mechanisms for this effect, and propose that mTOR-specific kinase inhibitors, instead of rapamycin, should be considered for mTOR-targeted cancer therapy.

Mammalian Target of Rapamycin Complex 1 (mTORC1) Plays a Role in Pasteurella multocida Toxin (PMT)-induced Protein Synthesis and Proliferation in Swiss 3T3 Cells

“…In fact, this notion has been challenged by the observation that a higher rate of protein synthesis occurred in knock-in mice whose ribosomal S6 protein contained alanine substitutions at all five phosphorylatable serine residues (46) and the translation of 5Ј terminal oligopyrimidine tract mRNAs was not impaired in S6K1 knock-out mice (47). The observed partial inhibitory effect of rapamycin on PMT-induced protein synthesis is also consistent with findings that whereas mTORC1 phosphorylates both S6K1 and 4E-BP1, rapamycin efficiently inhibits S6K1 phosphorylation but only partially inhibits the phosphorylation of 4E-BP1 (23,48,49).…”

Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony

“…Perhaps RhoE functions as an inhibitor of rapamycin-insensitive mTORC1? These findings overturn the long-standing presumption in the field that rapamycin inhibits all mTORC1 function completely (15,74,75).…”

“…Whereas rapamycin completely inhibits mTORC1-mediated S6K1 phosphorylation, rapamycin reduces 4EBP1 phosphorylation, protein synthesis, cell growth, and cell proliferation only incompletely and variably, depending on cell type (8,74,75). Moreover, whereas rapamycin strongly promotes autophagy in yeast, it does so only modestly in mammalian cells.…”

mTOR Kinase Domain Phosphorylation Promotes mTORC1 Signaling, Cell Growth, and Cell Cycle Progression

“…mTOR S2159/T2164 phosphorylation promotes cellular mTORC1 signaling to 4EBP1. Recent work indicates that while rapamycin partially inhibits mTORC1-mediated phosphorylation of 4EBP1, novel ATP-competitive mTOR kinase inhibitors completely block 4EBP1 phosphorylation, indicating that not all mTORC1 substrates are equally sensitive to rapamycin (11,12,16,66). Thus, rather than employing our RR-mTOR assay in conjunction with rapamycin treatment to study the role of mTOR S2159/T2164 phosphorylation in mTORC1 signaling to 4EBP1, we utilized AU1-mTOR alleles in a wild-type backbone in the absence of rapamycin treatment.…”